Download Points to consider in Preclincal Development

PARENTERAL DRUG
DELIVERY
Dr. Md. Harun Ar Rashid
Head,
Dept. of Pharmacy,
NUB
PARENTERAL PRODUCT
Dr. Md. Harun Ar Rashid
Head,
Dept. of Pharmacy,
NUB
Sterile Products:
 Sterile
products are dosage forms of
therapeutic agents that are free from microorganisms or their spores.
Based on the route of administration, sterile
products are classified into:
1.
2.
3.
4.
Parenteral preparations
Ophthalmic preparations
Otic preparations
Nasal preparations
- for the eye
- for the ear
- for the nose
& throat
5. Irrigating solutions
- for washing wounds
or abraded mucous membrane

Parenteral Products: Parenteral products are sterile dosage
forms that are injected into body tissues (into internal body
compartment) through one or more layers of skin or mucous
membrane.Therefore, they must be exceptionally pure and
free from physical, chemical and biological contaminants.
 Definitions
related to the topic:
-- Parenteral Products
– Sterilization & Sterile Product
– Pyrogen
– SVP
– LVP
– Light Resistant Containers
– Well closed containers
– Tightly closed containers
– Single dose container
– Multiple dose container
– Hermetically sealed container
PARENTERALS
para: outside
enteron: intestine (i.e. beside the intestine)
These are the preparations which are given other
than oral routes.
Injections:
These are
 Sterile,
 Pyrogen free preparations intended to be
administered parenterally (outside alimentary
tract).
Why Parenteral? Parenteral Route Is Used bcoz
1) Rapid action
2) Oral route can not be used
3) Not effective except as injection
4) Many new drugs particularly those derived from new
development in biotechnologically can only be given
by parenteral coz they are inactivated in GIT if given
orally.
5) New drugs require to maintain potency & specificity
so that they are given by parenteral.

Advantages:
– Quick onset of action
– Suitable for the drugs which are not administered
by oral route
– Useful for unconscious or vomiting patients.
– Duration of action can be prolonged by modifying
formulation.
– Suitable for nutritive like glucose & electrolyte.
– Suitable for the drugs which are inactivated in GIT
or HCl (GI fluid)

Disadvantages:
– Once injected cannot be controlled (retreat)
– Injections may cause pain at the site of injection
– Only trained person is required
– If given by wrong route, difficult to control adverse
effect
– Difficult to save patient if overdose
– Sensitivity or allergic reaction at the site of injection
– Requires strict control of sterility & non pyrogenicity than
other formulation.

BASIC REQUIREMENTS OF PARENTERAL
PRODUCTS
1. Must be free from viable micro-organisms or their spores.
2. Must be free from toxic components/pyrogens
3. Must be free from chemical contaminants.
4. Must be free from foreign particles such as dust, fibres.
5. Safety level of all the ingredients should be same and every
means of safety should be ensured including packaging
material.
6. The pH of the product should be strictly maintained. Adequate
buffers should be used.
7. Water used in parenteral products must be inert/sterilized.
8. Isotonicity of the product must be maintained.
9. Container of products must be free from pyrogens.
10.Water for injection should have conductivity < 1 μmho.

Necessities of Parenteral preparations:
– Sterility (must)
– Pyrogen (must)
– Free from particulate matter (must)
– Clarity (must)
– Stability (must)
– Isotonicity (should)
– Solvents or vehicles used must meet special purity and other
standards.
– Restrictions on buffers, stabilizers, antimicrobial preservative. Do not
use coloring agents.
– Must be prepared under aseptic conditions.
– Specific and high quality packaging.

PARENTERALS ARE ADMINISTERED BY:
Physician
 Physician’s assistant
 Nurse

PARENTERALS ARE ADMINISTERED AT:

Hospitals
 Clinics
 Extended care facilities
6 hypodermic needles on luer connectors;
from top to bottom: 26G × 1/2" (0.45 ×
12mm) (brown), 25G × 5/8" (0.5 × 16mm)
(orange), 22G × 1¼" (0.7 × 30mm) (black),
21G × 1½" (0.8 × 40mm) (green), 20G ×
1½" (0.9 × 40mm) (yellow), 19G × 1½"
(1.1 × 40mm) (white)
Routes of Parenteral Administration
Subcutaneous (21)
Intradermal (23)
Intravenous (21)
Intramuscular (20)
Intra arterial (20-22)
Epidermis
Dermis
Vein
Artery
Subcutaneous
tissue
Muscle
Parenteral Routes of Administration
1. Intradermal –
skin
2. Subcutaneous or Hypodermis
–
under the skin
3. Intramuscular –muscles
6. Intracardiac – heart
7. Intraspinal – spinal column
a. Intrathecal or subarachnoid
injection
b. Intra-cisternal injection
c. Peridural Injections
8. Intra-articular
– joints
4. Intravenous –veins
9. Intrasynovial – joint fluid
5. Intra-arterial –arteries
10. Intrapleural - lung
1.
Intracutaneous or Intradermal
# also called as diagnostic testing
# administrated into the skin between the
epidermis and dermis
# usual site is the anterior surface of the fore arm
# needle is inserted horizontally with the bevel
facing upward
# 0.1 – 0.2 ml due to poor vascularity of the site
# short 3/8 inch, 23 to 26 narrow gauge needle
# Should be isotonic

Given:
Diagnostic agents for immunity and allergy test e. g:
test for penicillin
2.Subcutaneous or Hypodermis(SC; SQ ;Sub Q):
 Utilized for




– the injection of small amounts of medication or of drugs
beneath the surface of the skin of the
1. upper arm,
2. the anterior surface of the thigh, and the
3. lower portion of the abdomen.
The site of injection is usually rotated when injections are
frequently given, as with daily insulin injection.
The maximum amount of drug given SC is about 1.3 mL
Amounts greater than 2 mL will most likely cause painful
pressure.
- ½ to 1 inch. 23 gauge needle or smaller needle is used
Continued.
*The route is not used for aqueous suspensions or
oily suspension and fluids.
* It is usually used for self-medication by the patient
* Upon insertion, if blood appears in the syringe, a
new site should be selected.
*Irritating drugs and those in thick suspension may
produce
- induration, sloughing, or abscess and may be
painful. Such preparations are not suitable for
subcutaneous injection.

Given: Vaccines, Insulin, Scopolamine, Epinephrine
3. Intramuscular (IM)

The route is used for aqueous and oily
suspensions and oily solutions,

Reduce Pain and irritation (subcutaneously),
blockage of small blood vessels (intravenously)
occur.

Intramuscular injections of drugs provide effects
that are less rapid, but generally of greater
duration than those obtained from intravenous
administration
 IM
are performed deep into the skeletal
muscles.

The point of injection should be as far as
possible from major nerves and blood vessels.
Injuries to patients from IM injection usually are
related to the point at which the needle entered
and where the medication was deposited.

Continued:

Such injuries include:
1. Paralysis resulting from neural damage
2. Abscesses
3. Cysts
4. Embolism
5. Hematoma
6. Sloughing of the skin
7. Scar formation

Principle sites:
– Gluteal (buttocks)
– Deltoid (upper arms)
– Vastus lateralis (lateral thigh)
Adult – upper outer quadrant of the gluteus
maximus
Infants– gluteal area is small, composed
primarily fats not muscle, so not recommended.
Infants and Young children – deltoid, muscles
of the upper arm or the midlateral muscles of
the thigh
Volume of Administration:
– 0.5 to 2 ml sometimes upto 4 ml
– 1 to 1.5 inch & 19 to 22 gauge needle is used
– Preferably isotonic
To avoid staining: it must be injected only into
the muscle mass of the upper outer quadrant of
the buttock.





The skin is displaced laterally, then needle inserted
and syringe aspirated, and injection performed slowly
and smoothly. The needle is then withdrawn and the
skin release. This create a “Z”pattern that blocks
infiltration of medication into subcutaneous tissue.
The Z-Track Injection techniques is useful for IM
injections of medications that stain upper tissue.
Examples:
Iron dextran injection –irritate tissues
Diazepam (Valium) – by sealing in the lower
muscle
4. Intravenous Route (IV)
Advantage:
 May be a life-saving procedure because of the
placement of the drug directly into the circulation and
the prompt actions which ensues.
Disadvantage:
 Once the drug administered, it cannot be retrieved.
 In the case of adverse reaction to the drug, for
instance, the drug cannot be easily removed from the
circulation.
Precautions:
 Strict aseptic precautions must be taken at all times to
avoid risk of infection.
 The syringes and needles used must be sterilized and
to the point of entrance must be disinfected to reduce
chance of carrying bacteria from the skin into the
blood via the needle
Intravenous Route (IV)
- Administered into the vein 1 to 1000 ml
- 1 inch , 19 to 20 gauge needle with injection rate 1ml /
10 sec. for volume upto 5 ml & 1 ml/ 20 sec.for volume
more than 5 ml.
- Great care must be taken to prevent overdosing or
underdosing
Given:
– Aqueous solutions
– Hydro alcoholic solutions
– Emulsions
– Liposome

IV infusion of large volume fluids (100- 1000 ml) has
become increasingly popular. This technique is called
as Venoclysis.

This is used to supply electrolytes & nutrients to
restore blood volume & to prevent tissue dehydration.

Combination of parenteral dosage forms for
administration as a unit product is known as an IV
admixture.
– Lactated Ringer Injection USP
– NaCl Injection USP (0.9 %)– (replenish fluid &
electrolyte)
– Dextrose Injection USP (fluid & electrolyte)
Intravenous fat emulsions


– Intralipid, 10,20,30%
– Clintec
– Liposyn 11,10, 20%
– Abott Liposyn 111, 10,20,30%
as a source of calories and essential fatty acids for
patients requiring parenteral nutrition for extended
period, usually more than 5 days.
The product contains up to:
30% soybean oil emulsified with egg yolk
phospholipids in a vehicle of glycerin in water injection



The possibility of thrombus formation
– induced by the touching of the wall of the vein by
the catheter or needle.
Thrombus
– is a blood clot formed within the blood vessel (or
heart) due usually to a slowing of the circulation or
to an alteration of the blood or vessel wall.
Once such a clot circulates, it becomes an Embolus
– carried by the blood stream until it lodges in a blood
vessel, obstructing it, and resulting in blockage or
occlusion referred to as an Embolism.
NOTE:
 Not only are the injectable solutions sterile, syringes,
needles must also be disinfected to reduce the chance
of carrying bacteria
 A backflow of blood into the administration set or
syringe indicates proper placement of the needle in
the vein
 Intravenous drugs ordinarily must be aqueous
solution;
they must mix with the circulating blood and not
precipitate from solution. Such an event can lead to
pulmonary micropillary occlusion and blockage of
blood flow.

5.Intra-arterial(IA)
Direct into the artery
– 2 to 20 ml
– 20 to 22 gauge
– Solutions & emulsions can be administered
 Given:
– Radio opaque media
– Antineoplastic
– Antibiotics
 Intra-arterial injections are similar to intravenous injection and
used occasionally for an immediate effect in a peripheral
organ.
*Such as - To improve circulation to the entremities when
arterial flow is restricted by arterial spasm or early
gangrene.
Example-:Tolazoline HCl, peripheral vasodilatorsis sometimes
used by this route.

Intracardial
– Directly given into the heart
– 0.2 to 1 ml
– 5 inch , 22 gauge needle


This route is used for emergencies condition only
when drugs are given directly into
muscle on
ventricles.
Example-:
- Stimulants, such as adrenaline or isoprenaline
sulphate.
- Cadiotonics
- Calcium salts as a calcium channel blockers
(7)Intra-spinal route:

These routes involve access into or around the spinal
cord. Single dose injections, not greater than 20 ml
are used.

Spinal cord is enclosed in three coats:
The outer one is known as the dura mater,
The middle one as the arachnoid and
The inner one as the pia mater.
The subarachnoid space lies between the arachnoid and
pia mater and contains C.S.f.
(a)Intrathecal or subarachnoid injection:



Intrathecal injections are made into the subarachnoid
space.
This route is used for spinal anesthetics and
antibiotics such as Streptomycin in the treatment of
tubercular meningitis (Mycobacterium T.B)
Specific gravity of such injection should maintain as
that of C.S.f so that it won’t be diffuse into the brain.
(c) Peridural Injections:

These are made into the peripheral space which
located between the durameter and the inner aspect
of vertebrae. This space extends through out the full
length of spinal cord.
e.g—localized anaesthetic
(b) Intra-cisternal injection
They are given in between the first and second
cervical vertebrae.
 This route is principally used to withdraw
cerebrospinal fluid for diagnostic purposes.
8)Intra-articular route:
 Intra-articular injections are made into the synovial
fluid which lubricates the articulating ends of bones in
a joint.
e.g—specially arthritis gout

– Given directly into the joints
– 2 to 20 ml
– 5 inch 22 gauge
– Must be isotonic
Given:
– Morphine
– Steroids
– NSAID’s
– Antibiotics
9. Intrapleural

– Given directly into the pleural cavity or lung
– Used for fluid withdrawal
– 2 to 30 ml
– 2 to 5 inch, 16 to 22 gauge needle
Given:
– Narcotics
– Chemotherapeutic agents
(10) Intra-bursal route

Intra-bursal injections are given into the bursare which
are small sacs of fluids between movable parts such
as tendons and bones.